A prodrug, also referred to as a precursor of a drug, refers to a compound which achieves pharmacological action after the conversion in an organism. A prodrug per se has no or little bioactivity, and releases an active agent after metabolism in vivo. The purpose of investigating and preparing a prodrug is to increase the bioavailability, modify the solubility, enhance the targeting properties, or reduce the toxicity or side effects of the parent drug. It is advantageous for many drugs, especially those having low bioavailability, poor water solubility or high toxic side effects, to be prepared into prodrugs. In general, it is required in clinic that a prodrug can be quickly dissociated into a ligand and a parent drug after entering the body, and the ligand is non-toxic. The parent drug thus released can exert pharmaceutical effects, and the non-toxic ligand is of no harm to the body.
Taxane drugs (including those in clinical stage) with antitumor activity have the following parent structures:
wherein R1 is H or methyl; R2 is H, methyl or acetyl; R3 is phenyl or OC(CH3)3.
Among these drugs, paclitaxel, docetaxel and cabazitaxel are most widely used in clinic.
NameParent StructureR1R2R3paclitaxel(II-1)HAcPhdocetaxel(II-1)HHOC(CH3)3cabazitaxel(II-1)MeMeOC(CH3)3larotaxel(II-2)AcOC(CH3)3tesetaxel(II-3)OC(CH3)3
Taxane drugs have good antitumor activity. However, they have poor water solubility and low oral bioavailability, and thus can only be administered via intravenous injection in clinic. In clinic, nonionic surfactants, such as polyethoxylated castor oil or Tween-80, are often added to this class of compounds as co-solvents to prepare an injection. Unfortunately, such surfactants usually cause side effects, such as vasodilatation, reduced blood pressure, liver toxicity, severe allergic reactions and the like, which highly limit the clinical application of taxane drugs. As such, many pharmacists worldwide have tried to solve this problem by formulation improvement and structural modification.
With respect to the preparations of paclitaxel, references can be referred to the following: in 1995, Robert et al. described “Stable oil-in-water emulsions incorporating a taxane (taxol) and method of making same” (CN 1153474); in 1996, Hairu Zhang et al. described “Water soluble powder for injection of paclitaxel and preparation method thereof” (CN 96112502); in 1998, J. M. Géczy described “Pharmaceutical compositions containing cyclodextrins and taxoids” (Application No./Patent No. 98811010); in 1999, Rubinfeld, Joseph et al. described “Water-miscible pharmaceutical compositions of paclitaxel” (CN99812662), Guoying Weng et al. described “Lipid compositions of paclitaxel and preparation method thereof” (CN0019039), Yingjin Yuan et al. described “Prodrugs of paclitaxel or docetaxel supported by polyethylene glycol” (CN00109748), in 2001, Junqi Pan et al. described “A nanosized magnetic targeting preparation of paclitaxel and preparation method thereof” (CN01128733); in 2002, Bin Zhu et al. described “A preparation method of a nanoparticle of paclitaxel” (CN02133333), Jialin Yan et al. described “A novel preparation of an antitumor drug—a microemulsion of paclitaxel” (CN02153674); in 2003, Yu Liu et al. described “A water soluble complex of an antitumor drug, paclitaxel, and preparation method thereof” (CN03119497); in 2006, Xianghua Liu et al. described “A composition of paclitaxel/docetaxel liposomes and preparation method thereof” (CN200610137900), Shihai Li et al. described “A lipid microsphere injection of paclitaxel and preparation method thereof” (CN200610165800), Xiuguo Zhang et al. described “An intravenous injection solution of paclitaxel and application thereof” (CN200610165508); in 2007, Yunqing Kang et al. described “A paclitaxel loaded sustained release microsphere prepared by supercritical fluids technology” (CN200710049845), Fang Li et al. described “A nanoparticle of paclitaxel and preparation and application thereof” (CN200710047767); and in 2008, Dingquan Yao et al. described “A water soluble injection composition of paclitaxel, preparation and application thereof” (CN200810232882), Yuling Liu et al. described “A lipid composition of paclitaxel” (CN200810168213). However, all the above preparations have several disadvantages, and the clinical application thereof is limited.
With respect to the preparations of docetaxel, references can be referred to the following: Immordino et al. prepared liposomes containing docetaxel through a film dispersion method (Immordino M L, Brusa P, Arpicco S. et al., Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing docetaxel, J. Controlled Release, 2003, 91 (4):417-429); LIVERSIDGE, Gary et al. prepared nanoparticulate preparations of docetaxel or analogue thereof (CN200680012670.9); Shaohui Zheng et al. investigated sub-microemulsion for intravenous injection of docetaxel and preparation method thereof (CN200610012102); Yuqing Xu et al. prepared a magnetic microsphere of docetaxel by a heat-curing method (Yuqing Xu, Xuemei Wen, A preparation method of a magnetic microsphere of docetaxel, Journal of Harbin Medical University, 2005, 39(6):537-539; Yuqing Xu, Xuemei Wen, a magnetic microsphere of docetaxel and preparation method thereof, CN200410044113); Zhenxin Du et al. prepared a lipid emulsion of docetaxel (Zhenxin Du, Xiulian Lu, Datao Li et al., A lipid emulsion containing docetaxel and preparation method thereof, CN 200510084055); Jakateet al. prepared fibrlnogen-coated olive oil droplets with a drug loading of 1.0 g/l (Jakate A S, Einhaus C M, DeAnglis A P. et al., preparation, characterization, and preliminary application of fibrinogen-coated olive oil droplets for the targeted delivery of docetaxel to solid malignancies, Cancer Res, 2003, 63(21):7314-7320); and Le Garreeet al. prepared a PVP-b-PDLLA polymeric micelle of docetaxel (Le Garree D, Gori S, Luo L. et al., Poly(N-vinylpyrrolidone)-block-poly(d,l-lactide) as new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation, J Controlled Release, 2004, 99(1):83-101). All the above technologies are attempts for solving problems of taxane drugs currently used in clinic by formulation means, but with limited success.
The only successful water soluble preparation of taxane drugs is Albumin-bound paclitaxel marketed in 2005. Although this preparation does not contain a high molecular solvent, bubbles can be easily produced during formulating before injection due to the surfactant properties of albumin, and thus its application is not convenient.
Meanwhile, pharmaceutical chemists have focused on structural modification of taxane drugs. The main strategy for preparing water soluble derivatives of taxane drugs is to introduce hydrophilic groups to the 2′-OH or 7-OH in paclitaxel. Due to the high steric hindrance of 7-OH in paclitaxel, dissociation is difficult to occur after introduction of the groups at this position, and thus the compound obtained is unlikely to be used as a prodrug. The 2′-OH in taxane drugs is considered as an essential pharmacological group, and introduction of the groups to this position would result in decrease of efficacy. But the steric hindrance at this position is low, which would facilitate the dissociation. Pharmaceutical chemists have prepared many derivatives of paclitaxel and docetaxel (see e.g., Margri N F, Kingston D G I. J Nat Prod, 1988, 51:298; Journal of Medicinal Chemistry (1989), 32(4), 788-92; U.S. Pat. No. 4,960,790; Zhao Z. Kingston D G I. J Nat Prod, 1991, 54:1607; Mathew A, Mejillano M R, et al., J Med Chem, 1992, 35:4230; Nicolaon K C, Riemer C, Kerr M A, et al., Nature, 1993, 364:464; Nicolaon K C, Guy R K, Pitsinos E N, et al., Angew Chem Int Ed Engl, 1994, 33:1583; Chemistry & Biology 1995, 2 (4):223-227; JP09110865; J. Med Chem. 2000, 43, 3093-3102; Mendleev. Commun., 2001, 11(6):276-217; Biological & Pharmaceutical Bulletin (2002), 25(5), 632-641; J. Org. Chem., 2003, 68, 4894-4896; U.S. Pat. No. 6,649,778; CN200410002722; JP2006193627; Alaoui A. E., Saha N., Schmidt F., Monneret C. New Taxol (paclitaxel) prodrugs designed for ADEPT and PMT strategies in cancer chemotherapy, Bioog Med. Chem., 2006, 14:5012-5019; Bioorg. Med. Chem. Lett. 17 (2007) 2894-2898; Pharmaceutical Research, 26(4):785-793, 2009; Bioconjugate Chem. 2009, 20, 2214-2221; Pharmaceutical Research, 2010, 27(2):380-389; J. Med. Chem., 1997, 40(26):4319-28; J. Med Chem., 1996, 39(7):1555-9; Journal of Tianjin University, 2000, 33(1):51-5; Chemical Journal of Chinese Universities, 2000, 21(3): 401-6; EP524093, 1993; WO9623779; WO9802426; U.S. Pat. No. 6,025,385; WO9914209; U.S. Pat. No. 6,136,808; US20020052403; CN200610171580; Wenting Du, Lan Hong, Tongwei Yao, et al, Synthesis and evaluation of water-soluble docetaxelprodrugs-docetaxel esters of malic acid, Bioorganic & Medicinal Chemistry, 2007, 15(18), 6323-6330; CN200510027736.9; CN200510040320; WO2009141738; Chemistry & Biology 1995, 2 (4):223-227). However, no further reports regarding the derivatives have been found.
Since no substantial progress has been achieved in the investigations of water soluble derivatives of paclitaxel and docetaxel, no reports on the water soluble derivatives of subsequent taxane drugs, i.e., cabazitaxel, larotaxel and tesetaxel, have been found.
Although much effort has been made to the structural modification of taxane drugs by pharmaceutical chemists, no taxane derivative having good water solubility and easy dissociation in vivo has been found.